Basic cancer research has focused on identifying the genetic changes that lead to cancer. This has led to major advances in understanding of the molecular and biochemical pathways that are involved in tumorigenesis and malignant transformation. But understanding of the cellular biology has lagged. While the effect of particular mutations on the proliferation and survival of model cells may be known, it is not known what the effects of such mutations will be on the actual cells involved in particular cancers.
In fact, many observations suggest that analogies between normal stem cells and tumorigenic cells may be appropriate. Both normal stem cells and tumorigenic cells have extensive proliferative potential and the ability to give rise to new (normal or abnormal) tissues. Both tumors and normal tissues are composed of heterogeneous combinations of cells, with different phenotypic characteristics and different proliferative potentials. Because most tumors have a clonal origin, tumorigenic cancer cells must give rise to phenotypically diverse progeny, including cancer cells with indefinite proliferative potential, as well as cancer cells with limited or no proliferative potential. This suggests that tumorigenic cancer cells undergo processes that are analogous to the self-renewal and differentiation of normal stem cells. It is well documented that many types of tumors contain cancer cells with heterogeneous phenotypes reflecting aspects of the differentiation that normally occurs in the tissues from which the tumors arise. The variable expression of normal differentiation markers by cancer cells in a tumor suggests that some of the heterogeneity in tumors arises as a result of the anomalous differentiation of tumor cells. Thus, tumorigenic cells can be thought of as cancer stem cells that undergo an aberrant and poorly regulated process of organogenesis analogous to that of normal stem cells.
Many pathways that are classically associated with cancer may also regulate normal stem cell development. For example, the prevention of apoptosis by enforced expression of the oncogene bcl-2 results in increased numbers of hematopoietic stem cells (HSC) in vivo, suggesting that cell death has a role in regulating the homeostasis of HSCs. Other signaling pathways associated with oncogenesis, such as the Notch, Sonic hedgehog (Shh) and Wnt signalling pathways, may also regulate stem cell self-renewal. One particularly interesting pathway that has also been shown to regulate both self-renewal and oncogenesis in different organs is the Wnt signalling pathway.
It has been suggested that stem cells themselves the target of transformation in certain types of cancer. Because stem cells have the machinery for self-renewal already activated, maintaining this activation may be simpler than turning it on de novo in a more differentiated cell. Also, by self-renewing, stem cells often persist for long periods of time, instead of dying after short periods of time like many mature cells in highly proliferative tissues. This means that there is a much greater opportunity for mutations to accumulate in individual stem cells than in most mature cell types. Restricted progenitors could potentially be transformed either by acquiring mutations that cause them to self-renew like stem cells, or by inheriting existing mutations from stem cells, such that only a single mutation is required in the progenitors to cause transformation.
Although stem cells are often the target of genetic events that are necessary or sufficient for malignant transformation, in other cases restricted progenitors or even differentiated cells may become transformed. In the case of spontaneously arising human leukemias it is likely that stem cells accumulate the mutations that are necessary for neoplastic proliferation; however, these mutations may accumulate in stem cells even while the effects of the mutations are expressed in restricted progenitors. That is, mutations that accumulate in stem cells may lead to neoplastic proliferation of primitive progenitors downstream of stem cells.
Methods of identifying and isolating stem cells and cancer stem cells are of great interest for the understanding of mechanisms that govern these cells, and for the development of therapeutic modalities that can be appropriately targeted for the treatment of cancers and modulation of stem cell growth and development.